Despite extensive physiologic investigation, the primary causes of type 2 diabetes mellitus remain unknown. In addition, the metabolic syndrome comprising hypertension, insulin resistance and dyslipidemia has increasingly been recognized as a major public health problem of unknown cause. Genetic and genomic approaches have the capacity to identify these elusive primary causes, thereby defining the pathophysiology of these diseases and identifying new opportunities for therapeutic intervention. Recent studies have implicated loss of mitochondrial function as a factor underlying type 2 diabetes mellitus. In this project, wei will pursue several distinct lines of investigation that bear on this point. First, we will investigate the possibility that impaired mitochondrial function can contribute not only to diabetes but to the other component of the metabolic syndrome. This will be accomplished by the investigation of rare families with known functional mitochondrial mutations, and by the investigation of patients with metabolic syndrome for mitochondrial defects. Second, we will investigate gene expression in the young offspring of diabetics to determine whether early insulin resistance is correlated with altered expression of genes involved in mitochondrial oxidative phosphorylation and mitochondrial copy number. Third, because mitochondria are one of the major sources of reactive oxygen species one possible explanation for loss of mitochondrial function in insulin resistance is acquire damage of mitochondrial DNA. We will investigate this possibility by comparing mitochondrial damage in insulin sensitive and resistant offspring of diabetic parents. Finally, the ability to obtain in vivo biochemical phenotypes of mitochondrial function by MRS provides a new opportunity to define intermediate phenotypes that may be closely related to the primary defect underlying the disease. These can markedly increase the power of genetic linkage studies. We will ascertain kindreds from Project 1 that are segregating extreme biochemical phenotypes, extend these kindreds and map the responsible lenes by analysis of linkage, with an aim to positionally clone these novel susceptibility genes.